While numerous antiepileptic drugs have a high likelihood of producing seizure freedom in new-onset epilepsy, refractory epilepsy by definition represents that 1/3rd of all epilepsy patients who cannot be successfully treated by AEDs, either alone or in combination, a situation that has persisted over decades despite the introduction of many new AEDs. However it has been widely hypothesized that some AEDs might be more effective used in combination, such that their action together exceeds the predicted sum of their individual effects, otherwise known as synergism. We recently published a large-scale retrospective human study that demonstrated that only a single combination of AEDs, lamotrigine (LTG) plus valproate (VPA), was significantly more effective in treating refractory epilepsy, potentially exhibiting synergism, while LTG in combination with carbamazepine (CBZ) appeared to be less effective than the sum of their parts, thus exhibiting antagonism. In this study, we wish to translate these clinical findings to an animal model of refractory epilepsy in order to understand the cellular mechanisms. We will first rigorously determine whether the efficacy of LTG/VPA represents true pharmacodynamic synergism, or results from a pharmacokinetic interaction. We will then seek evidence for a novel hypothesis as to the failure of most AED regimens in refractory epilepsy: that many AEDs constrain the excitability of inhibitory interneurons as well as excitatory principal neurons, and that this off-target action promotes AED refractoriness. The potential outcome of this study will be the translation from bedside- to-bench of a novel clinical finding-understanding the mechanisms of which could lead to an improved approach to AED design.